Osmolyte Effect on Aggregation of ß-Lactoglobulin Amyloid-Prone Peptides by Explicit Molecular Dynamics Simulation

Abstract

Whereas the toxicity of pathogenic amyloids relies on protein misfolding, other nonpathogenic or even functional amyloid structures can regulate physiological activity in a number of domains. Understanding the structural transition within this class of amyloids will provide insights into the general mechanism for ordered to agregation-dependent transitions. We have performed explicit molecular dynamics simulations using GROMACS with GROMOS53A6 force field and SPC water model. We have investigated 6 and 12 peptides of sequence: Ac-y146HIRLSFN152NH2, from bovine s-lactoglobulin; theses peptides are known to display high aggregation propensity under specific experimental conditions (5 M urea). We have shown by MD that the peptides form in water and in 5 M urea, in less than 100 ns, a structural aggregate displaying antiparallel s-sheets, with an hydrophobic core protected from water. Furthermore, we have examined the effect of two different osmolytes (2.5 and 5 M Urea and 1.5 M Trehalose) on the nature of the interactions favoring the s-structure of the peptidic-aggregates. The addition of each osmolyte or a mixture of both increases the conformational stability of the six peptide amyloid-prone aggregate. All the studied osmolytes, decrease the number of peptide-water hydrogen bonds, increase the peptide-osmolyte hydrogen bonds, while the number of the intrapeptide hydrogen bonds remains almost unchanged. This result is in good agreement with the suggested mechanism of osmolytes replacing water molecules on the peptide aggregate surface. In contrast our molecular dynamics simulation has uncovered that the conformational stability of the 12 peptide aggregate was very similar in water, in presence of each osmolyte or a mixture of both. This effect is most probably due to the higher content of intrapeptide hydrogen bonds existing in the hydrophobic core formed within the 12 peptide aggregate.